Targeting IDH2R140Q and other neoantigens in acute myeloid leukemia.

ABSTRACT: For patients with high-risk or relapsed/refractory acute myeloid leukemia (AML), allogeneic stem cell transplantation (allo-HSCT) and the graft-versus-leukemia effect mediated by donor T cells, offer the best chance of long-term remission. However, the concurrent transfer of alloreactive T cells can lead to graft-versus-host disease that is associated with transplant-related morbidity and mortality. Furthermore, ∼60% of patients will ultimately relapse after allo-HSCT, thus, underscoring the need for novel therapeutic strategies that are safe and effective. In this study, we explored the feasibility of immunotherapeutically targeting neoantigens, which arise from recurrent nonsynonymous mutations in AML and thus represent attractive targets because they are exclusively present on the tumor. Focusing on 14 recurrent driver mutations across 8 genes found in AML, we investigated their immunogenicity in 23 individuals with diverse HLA profiles. We demonstrate the immunogenicity of AML neoantigens, with 17 of 23 (74%) reactive donors screened mounting a response. The most immunodominant neoantigens were IDH2R140Q (n = 11 of 17 responders), IDH1R132H (n = 7 of 17), and FLT3D835Y (n = 6 of 17). In-depth studies of IDH2R140Q-specific T cells revealed the presence of reactive CD4+ and CD8+ T cells capable of recognizing distinct mutant-specific epitopes restricted to different HLA alleles. These neo-T cells could selectively recognize and kill HLA-matched AML targets endogenously expressing IDH2R140Q both in vitro and in vivo. Overall, our findings support the clinical translation of neoantigen-specific T cells to treat relapsed/refractory AML.

Interventional Pulmonology Productivity, Compensation, and Practice Benchmarks: The AABIP 2022 Report.

BACKGROUND: Interventional pulmonology (IP) is a growing field that has not yet been recognized by the American Board of Medical Specialties or incorporated into national benchmark organizations. As a result, there is a lack of data on IP practice patterns, physicians' compensation and productivity targets. METHODS: We sent an anonymous survey to 647 current or past physician members of the AABIP. Domains included demographics, training background, academic rank, practice settings, work relative value unit (wRVU) targets, salary, and career satisfaction. RESULTS: The response rate to the survey was 28.3%; 17.8% were female. The median salary for IP faculty in academic institutions was $320,000 for assistant professors, $338,000 for associate professors, and $350,000 for full professors. Salaries were lower for women than for men in academic practice, even after adjusting for the number of years in practice (mean salary difference after adjustment $57,175, 95% CI: $19,585-$94,764, P =0.003). The median salary for private practice was higher at $428,000. Among respondents that used wRVU targets, the median targets for academic and private practice were 5500 and 6300, respectively. The majority of IP physicians are satisfied with their career choice. CONCLUSIONS: Productivity targets in IP are used less than half the time, and when they are used, they are set in line with the lower wRVU of IP procedures. IP compensation is higher than that of general pulmonary medicine, as reported by national benchmark associations. In academic practices, gender differences in salaries were found.

Multi-antigen-targeted T-cell therapy to treat patients with relapsed/refractory breast cancer.

Purpose: Adoptively transferred, ex vivo expanded multi-antigen-targeted T cells (multiTAA-T) represent a new, potentially effective, and nontoxic therapeutic approach for patients with breast cancer (BC). In this first-in-human trial, we investigated the safety and clinical effects of administering multiTAA T cells targeting the tumor-expressed antigens, Survivin, NY-ESO-1, MAGE-A4, SSX2, and PRAME, to patients with relapsed/refractory/metastatic BC. Materials and methods: MultiTAA T-cell products were generated from the peripheral blood of heavily pre-treated patients with metastatic or locally recurrent unresectable BC of all subtypes and infused at a fixed dose level of 2 × 107/m2. Patients received two infusions of cells 4 weeks apart and safety and clinical activity were determined. Cells were administered in an outpatient setting and without prior lymphodepleting chemotherapy. Results: All patients had estrogen receptor/progesterone receptor positive BC, with one patient also having human epidermal growth factor receptor 2-positive. There were no treatment-related toxicities and the infusions were well tolerated. Of the 10 heavily pre-treated patients enrolled and infused with multiTAA T cells, nine had disease progression while one patient with 10 lines of prior therapies experienced prolonged (5 months) disease stabilization that was associated with the in vivo expansion and persistence of T cells directed against the targeted antigens. Furthermore, antigen spreading and the endogenous activation of T cells directed against a spectrum of non-targeted tumor antigens were observed in 7/10 patients post-multiTAA infusion. Conclusion: MultiTAA T cells were well tolerated and induced disease stabilization in a patient with refractory BC. This was associated with in vivo T-cell expansion, persistence, and antigen spreading. Future directions of this approach may include additional strategies to enhance the therapeutic benefit of multiTAA T cells in patients with BC.

Gut microbiota and age shape susceptibility to clostridial enteritis in lorikeets under human care.

BACKGROUND: Enteritis is a common cause of morbidity and mortality in lorikeets that can be challenging to diagnose and treat. In this study, we examine gut microbiota in two lorikeet flocks with enteritis (Columbus Zoo and Aquarium-CZA; Denver Zoo-DZ). Since 2012, the CZA flock has experienced repeated outbreaks of enteritis despite extensive diet, husbandry, and clinical modifications. In 2018, both CZA and DZ observed a spike in enteritis. Recent research has revealed that the gut microbiota can influence susceptibility to enteropathogens. We hypothesized that a dysbiosis, or alteration in the gut microbial community, was making some lorikeets more susceptible to enteritis, and our goal was to characterize this dysbiosis and determine the features that predicted susceptibility. RESULTS: We employed 16S rRNA sequencing to characterize the cloacal microbiota in lorikeets (CZA n = 67, DZ n = 24) over time. We compared the microbiota of healthy lorikeets, to lorikeets with enteritis, and lorikeets susceptible to enteritis, with "susceptible" being defined as healthy birds that subsequently developed enteritis. Based on sequencing data, culture, and toxin gene detection in intestinal contents, we identified Clostridium perfringens type A (CZA and DZ) and C. colinum (CZA only) at increased relative abundances in birds with enteritis. Histopathology and immunohistochemistry further identified the presence of gram-positive bacilli and C. perfringens, respectively, in the necrotizing intestinal lesions. Finally, using Random Forests and LASSO models, we identified several features (young age and the presence of Rhodococcus fascians and Pseudomonas umsongensis) associated with susceptibility to clostridial enteritis. CONCLUSIONS: We identified C. perfringens type A and C. colinum associated with lorikeet necrohemorrhagic enteritis at CZA and DZ. Susceptibility testing of isolates lead to an updated clinical treatment plan which ultimately resolved the outbreaks at both institutions. This work provides a foundation for understanding gut microbiota features that are permissive to clostridial colonization and host factors (e.g. age, prior infection) that shape responses to infection.

Coexpression of respiratory syncytial virus (RSV) fusion (F) protein and attachment glycoprotein (G) in a vesicular stomatitis virus (VSV) vector system provides synergistic effects against RSV infection in a cotton rat model.

Respiratory syncytial virus (RSV) is one of the most important causes of respiratory disease in infants, immunocompromised individuals, and the elderly. Natural infection does not result in long-term immunity, and there is no licensed vaccine. Vesicular stomatitis virus (VSV) is a commonly used vaccine vector platform against infectious diseases, and has been used as a vector for a licensed Ebola vaccine. In this study, we expressed the RSV fusion (F) protein, the RSV F protein stabilized in either a pre-fusion or a post-fusion configuration, the attachment glycoprotein (G), or the G and F proteins of RSV in combination in a VSV vector. Cotton rats were immunized with these recombinants intranasally or subcutaneously to test immunogenicity. RSV F stabilized in either a pre-fusion or a post-fusion configuration proved to be poorly immunogenic and protective when compared to unmodified F. RSV G provided partial protection and moderate levels of neutralizing antibody production, both of which improved with intranasal administration compared to subcutaneous inoculation. The most successful vaccine vector was VSV expressing both the G and F proteins after intranasal inoculation. Immunization with this recombinant induced neutralizing antibodies and provided protection from RSV challenge in the upper and lower respiratory tract for at least 80 days. Our results demonstrate that co-expression of F and G proteins in a VSV vector provides synergistic effects in inducing RSV-specific neutralizing antibodies and protection against RSV infection.

Advanced Diagnostic and Therapeutic Bronchoscopy: Technology and Reimbursement.

Advanced interventional pulmonary procedures of the airways, pleural space, and mediastinum continue to evolve and be refined. Health care, finance, and clinical professionals are challenged by both the indications and related coding complexities. As the scope of interventional pulmonary procedures expands with advanced technique and medical innovation, program planning and ongoing collaboration among clinicians, finance executives, and reimbursement experts are key elements for success. We describe advanced bronchoscopic procedures, appropriate Current Procedural Terminology coding, valuations, and necessary modifiers to fill the knowledge gap between basic and advanced procedural coding. Our approach is to balance the description of procedures with the associated coding in a way that is of use to the proceduralist, the coding specialist, and other nonclinical professionals.

Basic and Advanced Pleural Procedures: Coding and Professional Fees Update for Pulmonologists.

There is an evolution of pleural procedures that involve broadened clinical indication and expanded scope that include advanced diagnostic, therapeutic, and palliative procedures. Finance and clinical professionals have been challenged to understand the indication and coding complexities that accompany these procedures. This article describes the utility of pleural procedures, the appropriate current procedural terminology coding, and necessary modifiers. Coding pearls that help close the knowledge gap between basic and advanced procedures aim to address coding confusion that is prevalent with pleural procedures and the risk of payment denials, potential underpayment, and documentation audits.

The safety and clinical effects of administering a multiantigen-targeted T cell therapy to patients with multiple myeloma.

Multiple myeloma (MM) is an almost always incurable malignancy of plasma cells. Despite the advent of new therapies, most patients eventually relapse or become treatment-refractory. Consequently, therapies with nonoverlapping mechanisms of action that are nontoxic and provide long-term benefit to patients with MM are greatly needed. To this end, we clinically tested an autologous multitumor-associated antigen (mTAA)-specific T cell product for the treatment of patients with high-risk, relapsed or refractory MM. In this study, we expanded polyclonal T cells from 23 patients with MM. T cells whose native T cell receptors were reactive toward five myeloma-expressed target TAAs (PRAME, SSX2, MAGEA4, Survivin, and NY-ESO-1) were enriched ex vivo. To date, we have administered escalating doses of these nonengineered mTAA-specific T cells (0.5 × 107 to 2 × 107 cells/m2) to 21 patients with MM, 9 of whom were at high risk of relapse after a median of 3 lines of prior therapy and 12 with active, relapsed or refractory disease after a median of 3.5 prior lines. The cells were well tolerated, with only two transient, grade III infusion-related adverse events. Furthermore, patients with active relapsed or refractory myeloma enjoyed a longer than expected progression-free survival and responders included three patients who achieved objective responses concomitant with detection of functional TAA-reactive T cell clonotypes derived from the infused mTAA product.

Career Development Training for Interventional Pulmonary Fellows: Are They Ready for the Workforce?

BACKGROUND: Interventional pulmonary (IP) fellows spend ≥6 years of postgraduate medical education before IP training. Given the high employment attrition rates of early medical professionals, we investigated the IP fellows' self-assessed readiness for employment and the role of an intense preemployment educational intervention on improving the same. MATERIALS AND METHODS: Over 2 consecutive academic years, IP fellows nationally were invited to a mid-year career development symposium focusing on employment search strategy and early career development. Attendees were anonymously surveyed presymposium/postsymposium and 6 months later at graduation. Both quantitative and qualitative data were collected. Attendees' knowledge and skills were rated on a 5-point Likert scale. A control group of IP fellows that did not attend the symposium were also surveyed at graduation. RESULTS: In total, 53 of 55 attendees (96% response rate) completed the presymposium survey and 50 of 55 (91%) completed the final survey at graduation. Overall, 16 of 18 (89%) nonattendees also completed the final survey at graduation. IP Fellows reported low baseline self-assessment scores on all question domains. Scores increased significantly postsymposium and were sustained at graduation (P<0.05). At graduation, the average response score of symposium attendees was significantly higher than that of nonattendees (P=0.04). Overall, 84% reported that the symposium helped them with their employment search. CONCLUSION: Advanced IP fellows were not well-equipped for a strategic employment search and early career development at the onset of their IP fellowship training. Participation in an intense educational intervention significantly improved fellows' self-assessment scores, an effect that was sustained at 6 months.

Value-Based Proposition for a Dedicated Interventional Pulmonology Suite: An Adaptable Business Model.

Value-based care is evolving with a focus on improving efficiency, reducing cost, and enhancing the patient experience. Interventional pulmonology has the opportunity to lead an effective value-based care model. This model is supported by the relatively low cost of pulmonary procedures and has the potential to improve efficiencies in thoracic care. We discuss key strategies to evaluate and improve efficiency in interventional pulmonology practice and describe our experience in developing an interventional pulmonology suite. Such a model can be adapted to other specialty areas and may encourage a more coordinated approach to specialty care.

Fiducial marker placement for stereotactic body radiation therapy via convex probe endobronchial ultrasound: a case series and review of literature.

Convex probe endobronchial ultrasound (CP-EBUS) and stereotactic body radiotherapy (SBRT) are valuable tools in the diagnosis, staging, and treatment of thoracic malignancies. With widespread clinical adoption, novel uses of CP-EBUS beyond mediastinal diagnosis and staging continue to be discovered. SBRT is an attractive treatment strategy in early-stage lung cancer and oligo-metastatic disease of the chest when a surgical approach is either not feasible or desirable. Accurate application of SBRT is aided by the placement of radio-opaque fiducial markers (FM) to compensate for respiratory cycle movements. We describe eight patients with central thoracic lesions, either known or suspected to be malignant, who underwent EBUS bronchoscopy with lesion sampling and successful intralesional placement of modified FM via our technique, review the existing literature on this topic, and discuss the nuances of coding and billing aspects of FM placement.

CNVs affecting cancer predisposing genes (CPGs) detected as incidental findings in routine germline diagnostic chromosomal microarray (CMA) testing.

BACKGROUND: Identification of CNVs through chromosomal microarray (CMA) testing is the first-line investigation in individuals with learning difficulties/congenital abnormalities. Although recognised that CMA testing may identify CNVs encompassing a cancer predisposition gene (CPG), limited information is available on the frequency and nature of such results. METHODS: We investigated CNV gains and losses affecting 39 CPGs in 3366 pilot index case individuals undergoing CMA testing, and then studied an extended cohort (n=10 454) for CNV losses at 105 CPGs and CNV gains at 9 proto-oncogenes implicated in inherited cancer susceptibility. RESULTS: In the pilot cohort, 31/3366 (0.92%) individuals had a CNV involving one or more of 16/39 CPGs. 30/31 CNVs involved a tumour suppressor gene (TSG), and 1/30 a proto-oncogene (gain of MET). BMPR1A, TSC2 and TMEM127 were affected in multiple cases. In the second stage analysis, 49/10 454 (0.47%) individuals in the extended cohort had 50 CNVs involving 24/105 CPGs. 43/50 CNVs involved a TSG and 7/50 a proto-oncogene (4 gains, 3 deletions). The most frequently involved genes, FLCN (n=10) and SDHA (n=7), map to the Smith-Magenis and cri-du-chat regions, respectively. CONCLUSION: Incidental identification of a CNV involving a CPG is not rare and poses challenges for future cancer risk estimation. Prospective data collection from CPG-CNV cohorts ascertained incidentally and through syndromic presentations is required to determine the risks posed by specific CNVs. In particular, ascertainment and investigation of adults with CPG-CNVs and adults with learning disability and cancer, could provide important information to guide clinical management and surveillance.

Cost-Utility Study of Warfarin Genotyping in the VACHS Affiliated Anticoagulation Clinic of Puerto Rico.

OBJECTIVE: To evaluate the cost-utility of the pharmacogenetic-guided dosing of warfarin (PGx), when compared to the current dosing strategy. METHODS: A Markov model was developed to assess the impact of the genotypingguided warfarin dosing in a hypothetical cohort of patients. The model was based on the percentage of time patients spent within the therapeutic international normalized ratio (INR) range (PTTR). PTTR estimates and genotype distribution were derived from a cohort of patients (n = 206) treated in the Veteran Affairs Caribbean Healthcare System (VACHS) and from results of other research study. Costs, utilities and event probability data were obtained from the literature. Probabilistic and one-way sensitivity analyses were performed to explore the range of plausible results. Willingness to pay was established at $50,000 per Quality Adjusted Life Year (QALY) gained. RESULTS: According to our model, the PGx strategy showed a QALY increase of 0.0021, with an increase in total cost of $272. This corresponds to an incremental cost-utility ratio (ICUR) of $127,501, ranging from $95,690 to $148,611. One-way sensitivity analysis revealed that the ICURs were more sensitive to the cost of genotyping and the effect of genotyping on the PTTR. CONCLUSION: Our model suggests that the warfarin PGx was not superior to the standard of care dosing strategy in terms of cost-utility.

Investing in New Technology in Pulmonary Medicine: Navigating the Tortuous Path to Success.

The introduction of new technologies offers the promise to advance medicine. This occurs alongside improved efforts to control costs of health care by hospital administrators, the Centers for Medicare & Medicaid Services' (CMS) pivot to value programs, and commercial payers' efforts to reduce reimbursement. These trends present a challenge for the pulmonologist, among others, who must navigate increasingly complex and highly scrutinized evaluation processes used to secure new technology (NT). Health-care providers are turning toward value assessments while simultaneously tasked with the mission of offering state of the art technologies and services. Pulmonologists desiring NT are thus faced with increased scrutiny in their evaluation of costs and clinical data to support investments. Consideration of this scrutiny and further evidence to temper the evaluation will improve the likelihood of adoption and patient access to clinically impactful technology. The identification of this evidence may provide a comprehensive view of the clinical and economic benefits of such technologies to both administrators and pulmonary clinicians. It is imperative that all parties involved in the decision process work collaboratively to deploy value added and clinically impactful technologies. Although a physician group might invest in such NT, the capital required often leads such decisions to a larger organization such as a hospital, health-care system, or privately owned entity. This article aims to provide a framework for pulmonary clinicians to better understand the processes that purchasers use to evaluate NT, the pressures that influence their consideration, and what resources may be leveraged toward success.

Developing an Interventional Pulmonary Service in a Community-Based Private Practice: A Case Study.

Interventional pulmonology (IP) is a field that uses minimally invasive techniques to diagnose, treat, and palliate advanced lung disease. Technology, formal training, and reimbursement for IP procedures have been slow to catch up with other interventional subspecialty areas. A byproduct of this pattern has been limited IP integration in private practice settings. We describe the key aspects and programmatic challenges of building an IP program in a community-based setting. A philosophical and financial buy-in by stakeholders and a regionalization of services, within and external to a larger practice, are crucial to success. Our experience demonstrates that a successful launch of an IP program increases overall visits as well as procedural volume without cannibalizing existing practice volume. We hope this might encourage others to provide this valuable service to their own communities.

Capturing structured, pulmonary disease-specific data elements in electronic health records.

Electronic health records (EHRs) have the potential to improve health-care quality by allowing providers to make better decisions at the point of care based on electronically aggregated data and by facilitating clinical research. These goals are easier to achieve when key, disease-specific clinical information is documented as structured data elements (SDEs) that computers can understand and process, rather than as free-text/natural-language narrative. This article reviews the benefits of capturing disease-specific SDEs. It highlights several design and implementation considerations, including the impact on efficiency and expressivity of clinical documentation and the importance of adhering to data standards when available. Pulmonary disease-specific examples of collection instruments are provided from two commonly used commercial EHRs. Future developments that can leverage SDEs to improve clinical quality and research are discussed.

Endobronchial valve placement and balloon occlusion for persistent air leak: procedure overview and new current procedural terminology codes for 2013.

Unidirectional endobronchial valves, originally studied for potential treatment of emphysema, have emerged as a useful intervention for patients with persistent air leak from the lung. The procedure is accomplished via bronchoscopy in a patient who already has a chest tube in place for management of the air leak. It uses an occluding balloon to determine the specific airway(s) leading to the leak by impact on airflow and subsequent placement of removable valve(s) in one or more segment or subsegments to decrease flow across the leak to allow for healing of the fistula. Specific US Food and Drug Administration-approved criteria for placement and removal of these valves via a Humanitarian Device Exemption are discussed along with reported outcomes. Current Procedural Terminology codes effective for 2013 that are specific to the procedure are reviewed.

Electronic medical records: a practitioner's perspective on evaluation and implementation.

This article describes the initial and ongoing efforts of our pulmonary medicine practice to deploy an electronic medical records (EMR) system. Key factors in the vendor selection and implementation process included (1) identification and commitment to long-term goals for EMR; (2) dedicated resources, including both physician and nonphysician champions to lead the design and implementation teams; and (3) ample patience and time allotted to achieve the desired results: a fully functional system that enhances quality, improves operational efficiency, and reduces costs. An EMR scorecard including multiple system attributes was designed to facilitate vendor comparisons. Perseverance, patience, and compromise were necessary to overcome the challenge of changing the behavior of providers and support staff. We have accomplished improvements in workflow automation and reductions in staff hours, office supplies, file space, and transcription costs. Our system lacks pulmonary-specific templates and prompts for work flow and clinical decision making. We have directed internal resources and outsourced professional support to design these features as our practice strives to enhance our quality of care with pulmonary disease management that conforms to national guidelines.